Binding properties of mono- and dimeric pyridine dicarboxamide ligands to human telomeric higher-order G-quadruplex structures

Abstract

Here, we report on the in vitro binding properties of the known pyridine dicarboxamide G-quadruplex ligand 360A and a new dimeric analogue (360A)2A to human telomeric DNA higher-order G-quadruplex (G4) structures. This study points to original binding features never reported for G4 ligands, and reveals a greater efficiency for the dimeric ligand to displace RPA (a ssDNA binding protein involved in telomere replication) from telomeric DNA.

A Comparative Study on High Selectivities of Human Telomeric Dimeric G‐Quadruplexes by Dimeric G‐Quadruplex Binders

“…Although the bisquinolinium dimer with the longest polyether linker 3c and monomer 360 A had high thermals tabilization towards antiparallel G2T1, the derivative with the medium-length polyether linker 3b had 10.3-foldh ighert hermal stabilization for G2T1 versusG 1, whereas compounds 360 A and 3c had only 1.5-fold and1 .2fold higher thermals tabilization,r espectively.D imer (360 A) 2A , which has al ongerl inker,n ot only showed some thermals tabilization towards G1 (DT m = 10 8C) but also only had a2 -fold higher thermal stabilization for G2T1 versusG 1( DT m = 20 8C) and a2 .7-fold highert hermal stabilizationf or trimer G-quadruplexes versusG 1( DT m = 27 8C). [43] These results indicatet hat compound 3b also showedh igher thermals tabilization towards G2T1 than compound (360 A) 2A .I na ddition, compound 3b showedr elatively low DT m values: À0.7, À1.4, and 1.6 8C for c-myc, c-kit 1, and c-kit 2, respectively (see the Supporting Information, Figure S29). These results demonstrate that com-pound 3b imparted higher thermals tabilization towards anti-parallelG 2T1t han the four monomeric G-quadruplexes (G1, ckit 1, c-kit 2a nd c-myc) and dsDNA.…”

“…Two 360 A moieties in compound 3b might stack with two Gq uartet moieties of two contiguous G-quadruplex units ( Figure 5), [28] which resultsi n the highers electivity of compound 3b towards antiparallel G2T1 than that of compound 360 A.T wo binding modesw ere observedf or dimericc ompound (360 A) 2A ,w hich hadalonger linker;a ccordingly,t wo of its 360 A moieties bound in as andwich-likem anner at one of the G4 units and at hird residue inserted into the pocket between two contiguousG4u nits. [43]…”

“…[39][40][41][42] This family of bisquinoliniumd erivatives, which show high binding affinities to human telomeric G-quadruplex DNA and telomerase inhibition, inspired us to establish their affinities and selectivities for multimeric G-quadruplexes.A lthoughadimeric analogue (360 A) 2A has just been reported to bind higher-order G-quadruplexes (especially trimericG -quadruplexes), the adjustment of the length of the linker will possibly result in different binding modes and increaset he selectivity towards higher-order Gquadruplexes. [43] With this in mind, together with our recent research on polyether-tethered berberine dimers 1a-c [29,30] and dinickel-salphen complexes 2a-c, [28] three bisquinolinium dimers (3a-c)w ith different length polyether linkers were designed (Scheme 1), and we have evaluated their abilities to selectively bind and stabilize humant elomeric dimeric quadruplex DNA (G2T1), and we have analyzed their telomerase inhibition and antitumor activity.F urthermore, the interaction of these three kinds of polyether-tethered dimeric G-quadruplex ligands( 1a-c, 2a-c,a nd 3a-c)t owardsG 2T1 has been com-pared to enablet he design of improved dimeric quadruplex bindersa nd potential anticancer reagents that target higherorder G-quadruplexes.…”

BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers

“…Chemical compounds have been shown to stabilize multimeric G-quadruplexes in vitro and in vivo ( 36–40 ). Some complex chemical compounds with large molecular weight such as a zinc-finger-like chiral supramolecular complex ( 36 ), di-nickel-salphen linked by (–C–C–O) ( 26 , 37 , 38 ), and a triaryl-substituted imidazole derivative ( 39 ), were identified to bind to dimer G-quadruplex structures, which are constituted by two consecutive quadruplex units ( 30 , 40 ). However, their anti-tumor activity in vivo has been scarcely evaluated ( 23–26 , 36–38 , 40 ).…”

Intercalation of a Heterocyclic Ligand between Quartets in a G‐Rich Tetrahelical Structure

“…Although 360A is aw ell-established G-quadruplex stabilizer, which is presumed to stack on outer G-quartet(s), [10,11] no structural transformation of VK2 into aG -quadruplex was observed upon binding of 360A. Although 360A is aw ell-established G-quadruplex stabilizer, which is presumed to stack on outer G-quartet(s), [10,11] no structural transformation of VK2 into aG -quadruplex was observed upon binding of 360A.…”